Approximately 92 million US adults have at least one form of cardiovascular disease (CVD), with the annual direct health care cost of CVD and stroke estimated to exceed $315 billion. Among US Veteran?s, CVD is the leading cause of hospitalizations and a major cause of disability and according to the VA Health Services Research and Development, ~80% of Veteran?s present with more than two CVD risk factors. Atherosclerotic diseases are a predominate form of CVD. The severity and associated morbidity/mortality of which is determined not only by overall plaque burden, but also by the stability, or vulnerability, of plaques. Thus, a better understanding of the underlying mechanisms and cell types involved in the growth and stability of plaques is critical to inform novel therapies. ADP ribosylation factor 6 (Arf6) is a member of the RAS family of small GTPases that regulates cell proliferation and motility as well as membrane trafficking. Arf6 is involved in inflammatory and arterial functions related to atherosclerosis, including immune cell adhesion/activation, endothelial cell permeability and angiogenesis. However, a role for Arf6 in atherosclerosis has not been described. We aim to elucidate the effects of modulating whole body and tissue-specific Arf6 on plaque burden, composition and stability, as well as explore pharmacological Arf6 inhibition as an anti-atherosclerotic therapy.